Combination Chemotherapy Followed by Stem Cell Transplant and Isotretinoin in Treating Young Patients With High-Risk Neuroblastoma

July 15, 2015 updated by: Gesellschaft fur Padiatrische Onkologie und Hamatologie - Germany

Trial Protocol for the Treatment of Children With High Risk Neuroblastoma (NB2004-HR)

RATIONALE: Giving chemotherapy before an autologous stem cell transplant stops the growth of tumor cells by stopping them from dividing or by killing them. It also prepares the patient's bone marrow for the stem cell transplant. The stem cells are given to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. Giving isotretinoin after transplant may kill any remaining tumor cells. It is not yet known which combination chemotherapy regimen is more effective when given before a stem cell transplant and isotretinoin in treating neuroblastoma.

PURPOSE: This randomized clinical trial is studying two different combination chemotherapy regimens to compare how well they work when given before a stem cell transplant and isotretinoin in treating young patients with high-risk neuroblastoma.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

OBJECTIVES:

Primary

  • Compare the event-free survival of pediatric patients with high-risk neuroblastoma treated with standard induction chemotherapy vs topotecan hydrochloride-containing induction chemotherapy followed by myeloablative autologous stem cell transplantation and consolidation therapy with isotretinoin.

Secondary

  • Compare the overall survival of patients treated with these regimens.
  • Compare early response (complete response, very good partial response, partial response, mixed response, stable disease, and progression/relapse) after 2 courses of standard vs experimental induction chemotherapy (or after 60 days if the second course is not yet finished).
  • Compare response to standard vs experimental induction chemotherapy before autologous stem cell transplantation (or after 280 days if induction chemotherapy is not yet finished).
  • Compare the toxicity of standard vs experimental induction chemotherapy during courses 1 and 2 and the frequency of ≥ grade 3 toxicity during the last 6 courses of induction chemotherapy.
  • Compare the extent of initial surgery and best surgery (biopsy vs incomplete resection vs macroscopic complete resection) and the frequency of complications related to surgery (e.g., nephrectomy, bleeding, infection, or intestinal obstruction).
  • Compare the acute and long-term side effects of external-beam radiotherapy.
  • Correlate the activity of MIBG and whole-body radiation dose.
  • Collect and store tumor material in the tumor bank for future evaluation of other molecular markers (MYCN and status of chromosome 1p and 11q) and prognostic significant gene signatures.

OUTLINE: This is a multicenter study. Patients are stratified according to disease stage, lactate dehydrogenase (LDH) status, MYCN status, and age at diagnosis (stage 4 disease; LDH not elevated; any MYCN status; age at diagnosis 1-21 years vs stage 4 disease; LDH elevated; any MYCN status; age at diagnosis ≥ 1 but < 2 years vs stage 4 disease; LDH elevated; any MYCN status; age at diagnosis 2-21 years vs localized disease; MYCN amplification; age at diagnosis ≥ 6 months)

  • Induction chemotherapy: Patients are randomized to 1 of 2 induction chemotherapy arms.

    • Arm I (standard): Patients receive N5 chemotherapy comprising cisplatin IV continuously over 96 hours and etoposide phosphate IV continuously over 96 hours on days 1-4 and vindesine IV over 1 hour on day 1. Patients also receive filgrastim (G-CSF) subcutaneously (SC) once daily beginning on day 9 and continuing until blood counts recover. Patients then receive N6 chemotherapy comprising vincristine IV over 1 hour on days 1 and 8, dacarbazine IV over 1 hour on days 1-5, ifosfamide IV continuously over 120 hours on days 1-5, and doxorubicin hydrochloride IV over 4 hours on days 6 and 7. Patients also receive G-CSF SC once daily beginning on day 10 and continuing until blood counts recover. Treatment with N5 and N6 chemotherapy alternates every 21 days for 6 courses (N5 chemotherapy is given in courses 1, 3, and 5 and N6 chemotherapy is given in courses 2, 4, and 6).
    • Arm II (experimental): Patients receive N8 chemotherapy comprising cyclophosphamide IV over 1 hour on days 1-7, topotecan hydrochloride IV continuously over 168 hours on days 1-7, and etoposide phosphate IV over 1 hour on days 8-10. Patients also receive G-CSF SC once daily beginning on day 12 and continuing until blood counts recover. Treatment with N8 chemotherapy repeats every 21 days for 2 courses. Patients then receive N5 chemotherapy alternating with N6 chemotherapy as in arm I.
  • Surgery: Patients may undergo secondary surgery after completion of 4 or 6 courses of induction chemotherapy but prior to radiotherapy.
  • Radiotherapy (131I-MIBG therapy and external-beam radiotherapy [EBRT]): Patients with active residual primary tumor after the completion of induction chemotherapy undergo ^131I-MIBG therapy* prior to autologous stem cell transplantation (ASCT) and EBRT after ASCT.

NOTE: *Patients with MIBG negative neuroblastoma at initial diagnosis will only receive EBRT.

  • Myeloablative ASCT: Patients receive melphalan IV over 30 minutes on days -8 to -5, etoposide phosphate IV over 4 hours on day -4, and carboplatin IV over 1 hour on days -4 to -2. Patients undergo reinfusion of CD34+ stem cells on day 0. Patients also receive G-CSF SC or IV over 4 hours once daily beginning on day 2 and continuing until blood counts recover.
  • Consolidation therapy (isotretinoin)*: Beginning 30 days after ASCT, patients receive oral isotretinoin once daily on days 1-14. Treatment repeats every 28 days for up to 6 courses. Beginning 3 months later, patients receive an additional 3 courses of isotretinoin.

NOTE: *Isotretinoin must not be given concurrently with radiotherapy

After completion of study treatment, patients are followed every 6 weeks for 1 year, every 3 months for 4 years, and then every 6 months thereafter.

Study Type

Interventional

Enrollment (Anticipated)

360

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Germany
      • Aachen, Germany, D-52074
        • Recruiting
        • Kinderklinik - Universitaetsklinikum Aachen
        • Contact:
      • Augsburg, Germany, DOH-86156
        • Recruiting
        • Klinikum Augsburg
        • Contact:
          • Astrid Gnekow
          • Phone Number: 49-821-400-3603
      • Bayreuth, Germany, D-95445
        • Recruiting
        • Klinikum Bayreuth
        • Contact:
          • T. Rupprecht
          • Phone Number: 49-921-400-1400
      • Berlin, Germany, D-13353
        • Recruiting
        • Charite University Hospital - Campus Virchow Klinikum
        • Contact:
          • Gunter Henze
          • Phone Number: 49-30-450-660-31
      • Berlin, Germany, 13125
        • Recruiting
        • Helios Klinikum Berlin
        • Contact:
          • Lothar Schweigerer, MD
          • Phone Number: 49-30-9401-2345
      • Biefeld, Germany, 33617
        • Recruiting
        • Evangelisches Krankenhauus Bielfeld
        • Contact:
          • N. Jorch, MD
          • Phone Number: 49-52-177-278-050
      • Bonn, Germany, D-53113
        • Recruiting
        • Kinderklinik der Universitaet Bonn
        • Contact:
      • Braunschweig, Germany, 38118
      • Bremen, Germany, D-28205
      • Chemnitz, Germany, D-09116
        • Recruiting
        • Klinikum Chemnitz gGmbH
        • Contact:
          • Krause, MD
          • Phone Number: 49-371-3332-4124
      • Coburg, Germany, 96450
        • Recruiting
        • Klinikum Coburg
        • Contact:
          • Roland Frank, MD
          • Phone Number: 49-9561-22-5547
      • Cologne, Germany, D-50924
      • Cottbus, Germany, D-03048
        • Recruiting
        • Carl - Thiem - Klinkum Cottbus
        • Contact:
          • D Mobius, MD
          • Phone Number: 49-355-462336
      • Datteln, Germany, 45704
      • Detmold, Germany, D-32756
        • Recruiting
        • Klinikum Lippe - Detmold
        • Contact:
          • Klaus Wesseler, MD
          • Phone Number: 49-523-172-4511
      • Dortmund, Germany, D-44137
      • Dresden, Germany, D-01307
      • Duesseldorf, Germany, D-40225
        • Recruiting
        • Universitaetsklinikum Duesseldorf
        • Contact:
          • Arndt Borkhardt
          • Phone Number: 49-211-311-7990
      • Duisburg, Germany, D-47055
        • Recruiting
        • Klinikum Duisburg
        • Contact:
          • Ruef, MD
          • Phone Number: 49-203-733-2421
      • Erfurt, Germany, 99089
      • Erlangen, Germany, 91054
        • Recruiting
        • Universitaets - Kinderklinik
        • Contact:
          • W. Holter, MD
          • Phone Number: 49-9131-853-3118
      • Essen, Germany, D-45147
        • Recruiting
        • Universitaetsklinikum Essen
        • Contact:
          • Bernhard Kremens, MD
          • Phone Number: 49-201-723-2453
      • Frankfurt, Germany, D-60590
        • Recruiting
        • Klinikum der J.W. Goethe Universitaet
        • Contact:
      • Freiburg, Germany, D-79106
      • Giessen, Germany, D-35385
        • Recruiting
        • Kinderklinik
        • Contact:
          • Alfred Reiter, MD
          • Phone Number: 49-641-994-3420
      • Goettingen, Germany, D-37075
        • Recruiting
        • Universitaetsklinikum Goettingen
        • Contact:
          • M. Lakomek, MD
          • Phone Number: 49-551-398-600
      • Greiswald, Germany, 17487
        • Recruiting
        • Universitats - Kinderklinik
        • Contact:
      • Halle, Germany, D-06097
        • Recruiting
        • Universitaetsklinikum Halle
        • Contact:
          • Dieter Koerholz, MD
          • Phone Number: 49-345-557-2387
      • Halle, Germany, D-06110
        • Recruiting
        • Krankenhaus St. Elisabeth und St. Barbara
        • Contact:
          • G. Guenther, MD
          • Phone Number: 49-345-482-50
      • Hamburg, Germany, D-20246
        • Recruiting
        • University Medical Center Hamburg - Eppendorf
        • Contact:
      • Hannover, Germany, D-30625
      • Heidelberg, Germany, D-69120
      • Herdecke, Germany, 58313
        • Recruiting
        • Gemeinschaftskrankenhaus
        • Contact:
      • Homburg, Germany, 66421
        • Recruiting
        • Universitaetsklinikum des Saarlandes
      • Jena, Germany, D-07745
        • Recruiting
        • Universitaets - Kinderklinik
        • Contact:
          • Felix Zintl, MD
          • Phone Number: 49-3641-938-270
      • Karlsruhe, Germany, 76133
        • Recruiting
        • Staedtisches Klinikum Karlsruhe gGmbH
        • Contact:
          • A. Leipold
          • Phone Number: 49-721-974-3311
      • Kassel, Germany, D-34125
        • Recruiting
        • Klinikum Kassel
        • Contact:
          • Martina Rodehueser, MD
          • Phone Number: 49-561-980-3066
      • Kiel, Germany, D-24105
      • Koblenz, Germany, D-56065
        • Recruiting
        • Klinikum Kemperhof Koblenz
        • Contact:
          • M. Rister, MD
          • Phone Number: 49-261-499-2602
      • Krefeld, Germany, D-47805
        • Recruiting
        • Klinikum Krefeld GmbH
        • Contact:
          • S. Volpel, MD
          • Phone Number: 49-2151-32-2375
      • Ludwigshafen, Germany, 67065
        • Recruiting
        • St. Annastift Krankenhaus
        • Contact:
          • Barbara Selle, MD
          • Phone Number: 49-621-5702-4449
      • Luebeck, Germany, D-23538
      • Magdeburg, Germany, D-39120
        • Recruiting
        • Universitaetsklinkum Magdeburg der Otto-von-Guericke-Universitaet Magdeburg
        • Contact:
          • P. Vorwerk, MD
          • Phone Number: 49-394-672-791
      • Mainz, Germany, D-55101
        • Recruiting
        • Johannes Gutenberg University
        • Contact:
          • P. Gutjahr, MD
          • Phone Number: 49-6131-17-2112
      • Mannheim, Germany, D-68167
        • Recruiting
        • Staedtisches Klinik - Kinderklinik
        • Contact:
          • M. Duerken
          • Phone Number: 49-621-383-2243
      • Marburg, Germany, D-35043
        • Recruiting
        • Universitaetsklinikum Giessen und Marburg GmbH - Marburg
        • Contact:
          • H. Christiansen, MD
          • Phone Number: 49-6421-286-2671
      • Minden, Germany, D-32423
      • Muenster, Germany, D-48149
        • Recruiting
        • Klinik und Poliklinik fuer Kinder und Jugendmedizin - Universitaetsklinikum Muenster
        • Contact:
      • Munich, Germany, D-80337
        • Recruiting
        • Dr. von Haunersches Kinderspital der Universitaet Muenchen
        • Contact:
          • Irene Schmid, MD
          • Phone Number: 49-89-5160-7978
      • Munich, Germany, 80804
        • Recruiting
        • Krankenhaus Muenchen Schwabing
        • Contact:
          • Stefan Burdach, MD, PhD
          • Phone Number: 49-89-3068-2352
      • Neubrandenburg, Germany, 17036
        • Recruiting
        • Klinikum Neubrandenburg
        • Contact:
      • Nuremberg, Germany, 90419
        • Recruiting
        • Cnopf'sche Kinderklinik
        • Contact:
          • W. Scheurlen
          • Phone Number: 49-911-334-002
      • Oldenburg, Germany, 26133
      • Regensburg, Germany, 93049
        • Recruiting
        • Klinik St. Hedwig-Kinderklinik
        • Contact:
          • Ove Peters
          • Phone Number: 49-941-369-5404
      • Rostock, Germany, D-18057
      • Siegen, Germany, D-57072
      • St. Augustin, Germany, 53757
      • Stuttgart, Germany, D-70176
      • Trier, Germany, D-54290
        • Recruiting
        • Krankenanstalt Mutterhaus der Borromaerinnen
        • Contact:
          • Wolfgang Rauh, MD
          • Phone Number: 49-651-947-2654
      • Tuebingen, Germany, D-72076
        • Recruiting
        • Universitaetsklinikum Tuebingen
        • Contact:
          • Rupert Handgretinger, MD
          • Phone Number: 49-7071-298-2087
      • Ulm, Germany, D-89075
      • Wuerzburg, Germany, D-97080
      • Wuppertal, Germany, D-42283
        • Recruiting
        • Helios Kliniken Wuppertal University Hospital
        • Contact:
          • K. Sinha, MD
          • Phone Number: 49-202-896-2441
  • Switzerland
      • Aarau, Switzerland, CH-5001
        • Recruiting
        • Kantonsspital Aarau
        • Contact:
          • R. Angst
          • Phone Number: 41-62-838-4906
      • Basel, Switzerland, CH-4005
        • Recruiting
        • Universitaets-Kinderspital beider Basel
        • Contact:
      • Lucerne 16, Switzerland, CH-6000
        • Recruiting
        • Kinderspital Luzern
        • Contact:
          • U. Caflisch, MD
          • Phone Number: 41-41-205-11-11
      • St. Gallen, Switzerland, CH-9006
      • Zurich, Switzerland, CH-8032
        • Recruiting
        • University Children's Hospital
        • Contact:
          • Felix Niggli, MD
          • Phone Number: 41-44-266-7823

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 21 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

DISEASE CHARACTERISTICS:

  • Diagnosis of neuroblastoma according to any of the following criteria:

    • Histological diagnosis from tumor tissue
    • Presence of distinct neuroblastoma cells in the bone marrow and elevated catecholamine metabolites (HVA, VMA) in blood or urine

  • High-risk disease, meeting 1 of the following criteria:

    • Stage 4 disease, regardless of the MYCN status (1-21 years of age)
    • Stage 1-3 or 4S disease with MYCN amplification (6 months -21 years of age)

PATIENT CHARACTERISTICS:

  • Not pregnant or nursing
  • Fertile patients must use effective contraception (hormonal contraception or intra-uterine device [IUD])

PRIOR CONCURRENT THERAPY:

  • No concurrent participation in another clinical trial that would preclude the interventions or outcome assessment of this clinical trial
  • No other concurrent anticancer therapy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Event-free survival (EFS)

Secondary Outcome Measures

Outcome Measure
Overall survival (OS)
Impact of well established clinical and molecular risk factors on EFS and OS
Early response, measured after 2 courses of induction chemotherapy
Response to induction therapy, measured before autologous stem cell transplantation
Toxicity during the first 2 courses and the last 6 courses of induction chemotherapy
Impact of the extent of initial and best surgery on outcome and frequency of complications
Acute and late toxicity of radiotherapy
Correlation of MIBG activity with whole-body radiation dose
Molecular markers (MYCN and status of chromosome 1p and 11q)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Gesellschaft fur Padiatrische Onkologie und Hamatologie - Germany

Investigators

  • Study Chair: Frank Berthold, MD, Children's Hospital Medical Center, Cincinnati

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2007

Primary Completion (Anticipated)

December 1, 2016

Study Registration Dates

First Submitted

September 5, 2007

First Submitted That Met QC Criteria

September 7, 2007

First Posted (Estimate)

September 10, 2007

Study Record Updates

Last Update Posted (Estimate)

July 16, 2015

Last Update Submitted That Met QC Criteria

July 15, 2015

Last Verified

July 1, 2015

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • GPOH-NB2004-HR
  • EU-20661
  • CDR0000564820 (Registry Identifier: PDQ (Physician Data Query))
  • UNI-KOELN-161

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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